Systemic lupus erythematosus is a multisystem disorder, predominantly affecting females in the reproductive age group. Renal involvement in the form of glomerulonephritis (GN) is a frequent manifestation associated with high morbidity and morality. This research proposal addresses mechanisms underlying the pathogenesis and prevention of lupus GN. During the past several years, a murine model of spontaneous SLE, NZM2328 strain has been investigated. It has been established that autoantibody production, acute and chronic GN are distinct phenotypes, under unique genetic controls. Published and preliminary data demonstrate that autoantibody responses to dsDNA, DNA-histone or immune complex deposition in the kidney are not sufficient to cause GN. Chronic GN and renal failure are associated with increasing T cell infiltration in the kidney and activation of T and B cells in the regional lymph nodes. These data support the hypothesis that an immune response to kidney antigens is required for chronic GN and will be addressed in Specific Aim 1. The proposed experiments will make use of two congenic strains NZM2328. C57Lc4 and NZM2328. C57Lc1 that have unique phenotypes. An adoptive cell transfer model will be established to demonstrate the direct role of kidney reactive T cells in mediating chronic GN. Antibodies from nephritic mice will be used to identify potential target antigens for lupus nephritis. In addition, a model of accelerated SLE induced by thymectomy on day 3 of life (d3tx) has been established in NZM2328. The d3tx NZM2328 model shows that enhanced autoantibody responses are associated with increased glomerular immune complexes and acute GN in male and female mice. However, only female mice progress to chronic GN while males do not. This suggests gender dependent factors regulating the susceptibility to end organ damage and will be investigated in Specific Aim 2. The role of chemokines, cytokines and apoptosis in the kidneys will be studied. The proposed experiments will demonstrate that chronic GN and renal failure requires a T cell response to kidney antigens and the susceptibility to end organ damage is determined by gender. These studies will provide insights into pathogenesis of lupus nephritis and identify checkpoints for intervention in patients.